2-(3,5-Disubstituted-4-pyridyl)-4-(thienyl, thiazolyl or arylphenyl)-1,3-oxazoline compounds

ABSTRACT

Oxazoline compounds having a 3,5-disubstituted-4-pyridyl group in the 2-position and a thienyl, thiazolyl or an arylphenyl group in the 4-position are effective in controlling aphids, insects and mites.

CROSS-REFERENCE TO RELATED APPLICATIONS

This application claims the benefit of U.S. Provisional Application No.60/213,308, filed Jun. 22, 2000.

BACKGROUND OF THE INVENTION

This invention provides new 2-(4-pyridyl)-oxazoline compounds that areuseful as insecticides and acaricides. More particularly, the presentinvention concerns 2-(3,5-disubstituted-4-pyridyl)-1,3-oxazolinecompounds and certain of their stereoisomers. The invention alsoincludes new synthetic procedures and intermediates for preparing thecompounds, pesticide compositions containing the compounds, and methodsof controlling insects and mites using the compounds.

There is an acute need for new insecticides and acaricides. Insects andmites are developing resistance to the insecticides and acaricides incurrent use. At least 400 species of arthropods are resistant to one ormore insecticides. The development of resistance to some of the olderinsecticides, such as DDT, the carbamates, and the organophosphates, iswell known. But resistance has even developed to some of the newerpyrethroid insecticides and acaricides. Therefore a need exists for newinsecticides and acaricides, and particularly for compounds that havenew or atypical modes of action.

Certain 3-(3,5-disubstituted-4-pyridyl)-1H-1,2,4-triazoles with activityagainst mites and insects are disclosed in WO 00/24735.2-(Substituted-phenyl)-1,3-oxazolines with insecticidal activity aredisclosed in JP 4-89484, EP 0345775-A1, EP 0432661-A2, EP 0553623-A1, WO99/01443, WO 99/23081 and WO 98/47881. 2-Aryl- and2-heteroaryl-1,3-oxazolines with acaricidal and insecticidal activityare disclosed in JP 6-145169 and WO 99/65901. Arthropocidal2-(substituted-phenyl)-1,3-oxazolines are disclosed in WO 93/24470. Tothe applicants' knowledge, only one oxazoline product, etoxazole, hasbeen developed as a commercial acaricide. It would be highly desirableto discover related compounds of this mode of action that are morepotent, more selective or of broader spectrum in their activity and/orthat have improved toxicological and environmental properties.

SUMMARY OF THE INVENTION

This invention provides novel substituted pyridyl oxazoline derivativesespecially useful for the control of insects and mites.

More specifically, the invention provides novel insecticidally activecompounds of the formula (I)

wherein

R¹ represents H, (C₁-C₆) alkyl, (C₁-C₆) haloalkyl, (C₂-C₆) alkenyl,(C₂-C₆) alkynyl, or (C₁-C₆) alkoxyalkyl;

R² represents H, halogen, (C₁-C₆) alkyl, (C₁-C₆) haloalkyl, (C₁-C₆)alkoxy, (C₁-C₆) haloalkoxy;

Q is a group selected from

R³ represents H, halogen, (C₁-C₆) alkyl, (C₇-C₂₁) straight chain alkyl,hydroxy, (C₁-C₆) alkoxy, (C₁-C₆) haloalkyl, (C₁-C₆) haloalkoxy, (C₁-C₆)alkoxyalkyl, (C₁-C₆) alkoxyalkoxy, (C₂-C₆) alkenyl, (C₂-C₆) haloalkenyl,CN, NO₂, CO₂R⁶, CON(R⁶)₂, (C₃-C₆) cycloalkyl, S(O)_(m)R⁶, SCN, pyridyl,substituted pyridyl, isoxazolyl, substituted isoxazolyl, thienyl,substituted thienyl, thiazolyl, substituted thiazolyl, phenyl,substituted phenyl, —(CH₂)_(n)R⁶, —CH═CHR⁶, —C≡CR⁶, —CH₂OR⁶, —CH₂SR⁶,—CH₂NR⁶R⁶, —OCH₂R⁶, —SCH₂R⁶, —NR⁶CH₂R⁶,

R⁴ represents H, halogen, (C₁-C₆) alkyl, (C₁-C₆) alkoxy, (C₁-C₆)haloalkyl, (C₁-C₆) haloalkoxy, CN, CO₂R⁶, CON(R⁶)₂, (C₁-C₆)S(O)_(m)alkyl or (C₁-C₆)S(O)_(m) haloalkyl;

R⁵ represents

R⁶ is H, (C₁-C₆) alkyl, (C₁-C₆) haloalkyl, (C₂-C₆) alkenyl, (C₂-C₆)alkynyl, phenyl, or substituted phenyl;

R⁷ and R⁸ are independently Cl, F, methyl, halomethyl, methoxy, orhalomethoxy;

m is 0, 1, or 2; and

n is 1 or 2;

or a phytologically acceptable acid addition salt or N-oxide thereof.

Preferred compounds of formula (I) include the following classes:

(1) Compounds of formula (I) wherein R⁷ and R⁸ are independently F orCl.

(2) Compounds of formula (I) wherein R⁷ and R⁸ are both F or both Cl.

(3) Compounds of formula (I) wherein R¹ is H or methyl.

(4) Compounds of formula (I) wherein R² is H.

(5) Compounds of formula (I) wherein Q represents a group of the formula

where R⁴ and R⁵ are as defined in formula (I).

(6) Compounds of class (5) wherein Q represents a group of the

formulawhere R³ and R⁴ are as defined in formula (I).

(7) Compounds of formula (I) wherein R³ and R⁴ are independently H,halogen, (C₁-C₆) alkyl, (C₁-C₆) alkoxy, (C₁-C₆) haloalkyl or (C₁-C₆)haloalkoxy.

It will be appreciated by those skilled in the art that the mostpreferred compounds are generally those which are comprised of variouscombinations of the above preferred classes.

The invention also provides new processes and intermediates forpreparing compounds of formula (I) as well as new compositions andmethods of use, which will be described in detail hereinafter.

DETAILED DESCRIPTION OF THE INVENTION

Throughout this document, all temperatures are given in degrees Celsius,and all percentages are weight percentages unless otherwise stated.

Unless specifically limited otherwise, the terms “alkyl”, “alkenyl” and“alkynyl”, as well as derivative terms such as “alkoxy” and “alkanoyl”,as used herein, include within their scope straight chain, branchedchain and cyclic moieties. The terms “alkenyl” and “alkynyl” areintended to include one or more unsaturated bonds.

Unless specifically limited otherwise, the term “halogen”, as well asderivative terms such as “halo”, as used herein, refers to fluorine,chlorine, bromine, and iodine. Preferred halogens are fluorine andchlorine.

The terms “halomethyl”, “haloalkyl”, and “haloalkenyl” refer to methyl,alkyl, and alkenyl groups substituted with from one up to the maximumpossible number of halogen atoms. The terms “halomethoxy” and“haloalkoxy” refer to methoxy and alkoxy groups substituted with fromone up to the maximum possible number of halogen atoms.

The terms “substituted pyridyl,” “substituted isoxazolyl,” “substitutedthienyl,” and “substituted thiazolyl” refer to the ring systemsubstituted with one or more groups independently selected from halogen,(C₁-C₄) alkyl, (C₁-C₄) haloalkyl, CN, NO₂, phenyl, (C₁-C₄) alkoxy, or(C₁-C₄) haloalkoxy.

The term “substituted phenyl” refers to a phenyl group substituted withone or more groups independently selected from halogen, (C₁-C₁₀) alkyl,(C₁-C₇) haloalkyl, (C₁-C₇) hydroxyalkyl, (C₁-C₇) alkoxy, (C₁-C₇)haloalkoxy, phenoxy, phenyl, NO₂, OH, CN, (C₁-C₄) alkanoyl, benzoyl,(C₁-C₄) alkanoyloxy, (C₁-C₄) alkoxycarbonyl, phenoxycarbonyl, orbenzoyloxy.

Unless otherwise indicated, when it is stated that a group may besubstituted with one or more substituents selected from an identifiedclass, it is intended that the substituents may be independentlyselected from the class, provided that the substituents are stericallycompatible and the rules of chemical bonding and strain energy aresatisfied.

When R¹ is other than hydrogen, the compounds of this invention canexist as one or more stereoisomers. The various stereoisomers includegeometric isomers, diastereomers and enantiomers. Thus the compounds ofthe present invention include racemic mixtures, individual stereoisomersand optically active mixtures. It will be appreciated by those skilledin the art that one stereoisomer may be more active than the others.Individual stereoisomers and optically active mixtures may be obtainedby selective synthetic procedures, by conventional synthetic proceduresusing resolved starting materials or by conventional resolutionprocedures.

Synthesis

Compounds of formula (I) can be prepared by the method shown in SchemeA:

wherein Q, R¹, R⁷ and R⁸ are as defined in formula (I).

The starting material of formula (A) used in Scheme A can be prepared byreacting the lithium salt of an appropriate isonicotinic acid withthionyl chloride in 1,2-dichloroethane at reflux.

In step a of Scheme A, the compound of formula (A) can be reacted withan aminoacid ester (J. Org. Chem. 1991, 56, 420) to afford a compound offormula (B). 1,2-Dichloroethane is the preferred solvent, however otherpolar aprotic solvents such as pyridine or THF can also be used.

In step b of Scheme A, the compound of formula (B) can be reacted with areducing agent such as sodium borohydride to afford a compound offormula (C) in an organic solvent such as ethanol, at a temperature inthe range from 0° C. to ambient temperature.

In step c of Scheme A, the compound of formula (A) can be reacted withan aminoalcohol (D) to afford a compound of formula (C).1,2-Dichloroethane is the preferred solvent, however other polar aproticsolvents such as pyridine or THF can also be used.

In step d of Scheme A, the N-amidealcohol of formula (C) can be reactedwith either (diethylamino)sulfur trifluoride (DAST) to provide theproduct of formula (I) or with thionyl chloride. The ring closurereaction is carried out in dichloromethane, 1,2-dichloroethane or neatat a temperature in the range from −78° C. to ambient temperature.

Alternatively, when Q represents

compounds of formula (I) can be prepared by the method shown in SchemeB:

wherein Q, R¹, R⁴, R⁵, R⁷ and R⁸ are as defined in formula (I).

In step a of Scheme B, the oxazoline of formula (Ia) is reacted understandard Suzuki coupling reaction conditions with an appropriatelysubstituted R⁵-boronic acid to provide the product of formula (Ib). Thecoupling reaction is carried out in an acetonitrile/water mixture, orethanol, at a temperature in the range from ambient to refluxingtemperature. Catalytic amounts ofdichlorobis(triphenylphosphine)palladium(II) ortetrakis(triphenylphosphine)-palladium(0) are typically used forcoupling, however other Pd(II) or Pd(0) catalysts can also be used.Typically sodium carbonate is used as base in the coupling reaction butother inorganic or organic bases such as potassium carbonate ortriethylamine can also be used.

When R¹ does not represent H, compounds of formula (I), in particulardiastereomers Syn (I) and Anti (I) can be prepared by the methodillustrated in Scheme C:

wherein R¹, Q, R⁷ and R⁸ are as defined in formula (I) provided that R¹does not represent H.

In step a of Scheme C, the compound of formula (A) is reacted with anaminoalcohol (D) to afford a compound of formula (C). 1,2-Dichloroethaneis the preferred solvent, however other polar aprotic solvents such aspyridine or THF can also be used.

The ring closure step b of Scheme C is similar to step d of Scheme A andprovides the products of formula Syn (I) and Anti (I) which can beseparated by using chromatographic techniques.

Alternatively, when Q represents

compounds of formula (I), in particular diastereomers Syn (Ib) and Anti(Ib), can be prepared by the method shown in Scheme D:

wherein R¹, Q, R⁴, R⁵, R⁷ and R⁸ are as defined in formula (I) providedthat R¹ does not represent H.

The Suzuki coupling step a of Scheme D is similar to step a of Scheme Band provides products of formula Syn (Ib) and Anti (Ib) which can beseparated by using chromatographic techniques.

Compounds of formula (D) can be prepared by the method illustrated inScheme E:

In step a of Scheme E, the compound of formula (E) is reacted with amixture of potassium acetate and tetrabutylammonium chloride atrefluxing temperature of dichloroethane to afford a compound of formula(F). Dichloroethane is the preferred solvent, however other chlorinatedsolvents such as dichloromethane or carbon tetrachloride can be used.Alternatively the transformation can also be carried out using inorganicacetates such as sodium acetate with other phase transfer catalysts suchas tetrabutylammonium bromide or iodide.

In step b of Scheme E, the compound of formula (F) is reacted withpotassium acetate in ethanol followed by treatment with methoxylaminehydrochloride to provide the compound of formula (G).

In step c of Scheme E, the compound of formula (G) is reacted with areducing agent such as sodium borohydride in trifluoroacetic acid toprovide the compound of formula (D) in an organic solvent such astetrahydrofuran. The reaction can be performed at ambient to refluxingtemperature. The product can be isolated as a salt, preferably as theHCl salt.

EXAMPLES Preparation of Starting Materials of Formula (D)

A) 4-[(1-Amino)-(2-hydroxy)ethyl]-iodobenzene (HCl salt)

2′-Bromo-4-Iodoacetophenone

A 1 L round bottom flask, equipped with a mechanical stirrer, additionfunnel, thermocouple and a reflux condenser attached to an alligatortrap filled with aq. NaOH (2M), was charged with CuBr₂ (92.4 g, 0.414mol) and ethyl acetate (320 mL). 4-Iodoacetophenone (53.4 g, 0.217 mol)was dissolved into chloroform (320 mL) and placed into the additionfunnel. The chloroform solution was added to the ethyl acetate solutionand the reaction mixture stirred at 70° C. for 6 hours then cooled to25° C. for 16 hours. The CuBr salt was removed by filtering throughCelite. The filtrate was washed with aq. saturated sodium bicarbonate(2×200 mL) and brine (100 mL). The organic layer was dried over sodiumsulfate, filtered, and the solvents were removed under reduced pressureto give crude product contaminated with unreacted starting material. Theproduct was purified by recrystallization from dichloromethane/hexane togive pure material as a tan solid (44.5 g, 63% yield): mp 109-111° C.2′-Acetoxy-4-iodoacetophenone

A 1 L round bottom flask equipped with a mechanical stirrer,thermocouple, and a reflux condenser was charged with2′-bromo-4-iodoacetophenone (44.0 g, 0.135 mol), potassium acetate (19.9g, 0.203 mol), benzyl triethylammonium chloride (1.5 g, 0.007 mol) and1,2-dichloroethane (425 mL). The reaction mixture stirred at 70° C. for4 hours then was cooled to 25° C. Water (250 mL) was added and thecontents were shaken in a separatory funnel. The dichloroethane layerwas separated and was washed with aq. saturated sodium bicarbonate (200mL) and brine (100 mL). The dichloroethane was dried over sodiumsulfate, filtered, and the solvents were removed under reduced pressureto give product as a tan solid (41.2 g, 97% yield): mp 103-107° C.4-[(2-Acetoxy)-(1-methoxyimino)ethyl]-iodobenzene

A 2 L round bottom flask equipped with a mechanical stirrer,thermocouple, and a reflux condenser was charged with2′-acetoxy-4-iodoacetophenone (35.9 g, 0.118 mol), potassium acetate(13.9 g, 0.142 mol), methoxylamine hydrochloride (11.8 g, 0.142 mol) andethyl alcohol (700 mL). The reaction mixture stirred at 70° C. for 8hours then cooled to 25° C., and stirred at this temperature for 16hours. The reaction mixture was filtered through Celite. The ethylalcohol was removed under reduced pressure and the residue dissolvedinto ethyl acetate (500 mL). Water (100 mL) was added and the contentswere shaken in a separator funnel. The ethyl acetate layer was separatedand was washed with aq. saturated sodium bicarbonate (2×100 mL) andbrine (100 mL). The ethyl acetate layer was dried over sodium sulfate,filtered, and the solvents were removed under reduced pressure to giveproduct as an oil (37.4 g, 95% yield). Product is a 4:1 mixture ofmethoxime isomers.4-[(1-Amino)-(2-hydroxy)ethyl]-iodobenzene (HCl salt)

A 250 mL round bottom flask equipped with a magnetic stirrer, additionfunnel, thermocouple, and a reflux condenser was charged with NaBH₄(4.54 g, 0.120 mol) and THF (100 mL). Trifluoroacetic acid (13.7 g, 9.3mL, 0.120 mol) was placed into the addition funnel and slowly added tothe NaBH₄ suspension. A solution of4-[(2-acetoxy)-(1-methoxyimino)ethyl]-iodobenzene (10.0 g, 0.030 mol) in20 mL of THF was added to the addition funnel, and then slowly added tothe trifluoroacetoxyborohydride suspension. The reaction mixture washeated to 70° C. for 3 hours and then cooled to 25° C. The pH wasadjusted to <3 by the careful addition of conc. HCl to neutralize theremaining NaBH₄. The pH was adjusted to >9 with 50% aq. NaOH. Water (100mL) and dichloromethane (200 mL) were added and the phases wereseparated. The aqueous phase was extracted with dichloromethane (3×100mL). The combined organic phases were washed with brine, dried oversodium sulfate, filtered, and the solvents were removed under reducedpressure to give crude product. The product was purified by suspendingin dichloromethane and bubbling anhydrous HCl gas to produce the HClsalt. The salt was filtered and dried to give product as a white solid(6.5 g, 72% yield): mp 200-206° C.

B) 2-Hydroxy-1-(4-iodophenyl)propanaminium chloride

1-Bromoethyl-(4-iodophenyl)ketone

Finely powdered cuprous bromide (20.21 g, 91 mmol) was suspended inethyl acetate (30 mL) and heated to reflux. A solution of ketone (14 g,54 mmol) in chloroform (30 mL) was added dropwise over 10 minutes. Afterrefluxing for 7 hours, the reaction was left to cool overnight andfiltered through Celite. The filtrate was washed with saturated aqueoussodium bicarbonate (2×50 mL) and brine (50 mL), dried over magnesiumsulfate and concentrated under reduced pressure. Recrystallization fromhexane afforded a pale yellow solid. mp 76° C. Yield 12.2 g (66%). ¹HNMR (CDCl₃) δ 7.83 (d, 2H), 7.72 (d, 2H), 5.21 (q, 2H), 1.87 (d, 3H).MI=338. IR (Liq film) cm⁻¹ 1677. Calculated for C₉H₈BrIO: C, 31.9%; H,2.38%. Found: C, 32.2%; H, 2.5%.1-Acetoxyethyl-(4-iodophenyl)ketone

A suspension of the bromoketone (12 g, 35 mmol), potassium acetate (5.2g, 53 mmol) and benzyl triethylammonium chloride (0.27 g, 1.2 mmol) in1,2-dichloroethane (75 mL) was refluxed under nitrogen for 6 hours.After cooling to room temperature, water (35 mL) was added and theorganic layer was collected. The organic layer was washed with saturatedaqueous sodium bicarbonate (30 mL), and brine (20 mL), dried overmagnesium sulfate and concentrated under reduced pressure to leave ayellow orange liquid. This was applied to a silica column and elutedwith 5:1 hexane/ethyl acetate. Concentration of the major fraction gave9.8 g (87%) of a pale yellow liquid. ¹H NMR (CDCl₃) δ 7.84 (d, 2H), 7.64(d, 2H), 5.87 (q, 2H), 2.14 (s, 3H), 1.56 (d, 3H). MI=318. IR (Liq film)cm⁻¹ 1740, 1699. Calculated for C₁₁H₁₁IO₃: C, 41.5%; H, 3.49%. Found: C,41.04%; H, 3.60%.2-Acetoxy-3-hydroxyamino-3-(4-iodophenyl)propane

To a solution of the acetate (4.5 g, 14 mmol) in absolute ethanol (80mL) was added potassium acetate (1.66 g, 17 mmol) and methoxylaminehydrochloride (1.41 g, 17 mmol). The reactants were stirred undernitrogen at 63° C. for 10 hours and then refluxed for 3 hours. Aftercooling to room temperature and filtration through Celite, the filtratewas concentrated under reduced pressure. The residue was taken up inethyl acetate (45 mL) and washed with water (15 mL), saturated aqueousbicarbonate (2×15 mL), and brine (20 mL) before drying over magnesiumsulfate. Concentration under reduced pressure afforded 4.45 g (91%) ofpale, yellow liquid. ¹H NMR (CDCl₃) δ 7.75 & 7.69 (both d, 2H in total),7.30 & 7.12 (d, 2H), 6.15 & 5.68 (q, 2H), 4.01 & 3.87 (s, 3H), 2.05 &1.90 (s, 3H), 1.60 & 1.41 (d, 3H). MI=347. IR (Liq film) cm⁻¹ 1743.2-Hydroxy-1-(4-iodophenyl)propanaminium chloride

Sodium borohydride (0.44 g, 11.5 mmol) was suspended in drytetrahydrofuran (10 mL) and cooled in an ice bath. Trifluoroacetic acid(1.31 g, 0.89 mL, 11.6 mmol) was then added dropwise over 10 minutes.The cooling bath was removed and a solution of the oxime (1 g, 2.9 mmol)in dry tetrahydrofuran (10 mL) was added over 10 minutes. The reactionwas refluxed under nitrogen for 14 hours, cooled to room temperature andacidified to pH 3.0 using concentrated hydrochloric acid. After coolingin an ice bath, 50% aqueous sodium hydroxide was added to bring the pHto 11. A mixture of methylene chloride (20 mL) and water (20 mL) wasthen added to the reaction mixture. The organic layer was collected andthe aqueous layer was re-extracted with methylene chloride (2×20 mL).The combined organic layers were washed with water (2×15 mL) and brine(15 mL) and dried over magnesium sulphate. Concentration under reducedpressure left a clear liquid that was taken up in methylene chloride (20mL). Dry hydrogen chloride gas was bubbled through this solution for 15minutes before stirring at room temperature for 30 minutes. White solidswere collected by filtration. Yield 0.25 g (28%). ¹H NMR (CDCl₃) δ 8.52(br, 3H), 7.79 (m, 2H), 7.31 (m, 2H), 5.68 & 5.39 (d, total 1H), 4.18 &3.96 (m, total 2H), 0.94 (s, 3H). MI=278.

C) 1-(4-Bromo-2-methylphenyl)-2-hydroxyethanaminium chloride

Ethyl (4-bromo-2-methylphenyl)(oxo)acetate

To a suspension of AlCl₃ (20.3 g, 152 mmol) in dichloroethane (250 mL,DCE) was added ethyl chlorooxoacetate (16.8 g, 123 mmol) at roomtemperature. To the resulting gold solution was added 3-bromotoluene(20.0 g, 117 mmol) and the dark solution was stirred at room temperaturefor 4 h. The reaction was cooled to 0° C. and saturated aqueous ammoniumchloride was slowly added. The phases were separated and the DCE layerwas washed with additional ammonium chloride, dried (Na₂SO₄), filtered,and the DCE removed in vacuo to give the crude product as a gold oil.Flash chromatography (SiO₂; 0-3% Et₂O/Hexanes) gave ethyl(4-bromo-2-methylphenyl)-(oxo)acetate (16.2 g; 33%) as a gold oil. ¹HNMR (CDCl₃) δ 1.41 (t, 3H, J=7.0 Hz), 2.58 (s, 3H), 4.43 (q, 2H, J=7.0Hz), 7.44-7.48 (m, 2H), 7.58 (d, 1H, J=8.0 Hz); EI/MS 271 m/e (M⁺).Ethyl (4-bromo-2-methylphenyl)-(methoxyimino)ethanoate

To a mixture of ethyl (4-bromo-2-methylphenyl)(oxo)acetate (10.0 g, 36.9mmol) and KOAc (4.71 g, 48.0 mmol) in EtOH (185 mL) was addedmethoxylamine hydrochloride (4.00 g, 48.0 mmol) and the resulting milkysuspension was stirred at 70° C. for 4 h. An additional 0.6 equivalentsof KOAc and methoxylamine hydrochloride were added and the reactionmixture was stirred at 70° C. for 16 h. The reaction mixture wasfiltered through Celite, and the EtOH was removed under reducedpressure. The residue was dissolved into ethyl acetate (250 mL) andwashed with aq. saturated sodium bicarbonate (2×100 mL) and brine (100mL). The ethyl acetate layer was dried over Na₂SO₄ and filtered and thesolvents were removed in vacuo to give the product as a colorless oil(11.0 g, 99%). Product is approximately a 1:1 mixture of methoximeisomers. ¹H NMR (CDCl₃) δ 1.30-1.36 (m, 6H), 2.16 (s, 3H), 2.43 (s, 3H), 4.01 (s, 3H), 4.04 (s, 3H), 4.30-4.38 (m, 4H), 6.98 (d, 1H, J=8.2Hz), 7.22 (d, 1H, J=8.2 Hz), 7.33-7.40 (m, 4H).1-(4-Bromo-2-methylphenyl)-2-hydroxyethanaminium chloride

To a suspension of NaBH₄ (5.56 g, 147 mmol) in THF (100 mL) was addeddropwise trifluoroacetic acid (16.7 g, 147 mmol) at a rate whichmaintained the reaction temperature between 25 and 35° C., and theresulting slurry was stirred at room temperature for 30 minutes. To thetrifluoroacetoxyborohydride suspension was added a solution of ethyl(4-bromo-2-methylphenyl)-(methoxyimino)ethanoate (11.0 g, 36.7 mmol) in20 mL of THF. The resulting light yellow mixture was stirred at refluxfor 3.5 h and then at room temperature for 16 h. The excess NaBH₄ wasneutralized by the careful addition of conc. HCl (pH<3). The pH wasadjusted to >9 with 50% aq. NaOH and the alkaline mixture was dilutedwith water (100 mL). The THF was evaporated and the aq. residue wasextracted with CH₂Cl₂ (3×100 mL). The organic extracts were washed withbrine, dried (Na₂SO₄), filtered, and the CH₂Cl₂ was removed in vacuo togive crude product as a yellow oil. The oil was dissolved in CH₂Cl₂ andanhydrous HCl was bubbled into the solution. The resulting HCl salt wascollected by vacuum filtration and dried to give the desired product asa white solid (5.7 g, 58%). mp 211-214° C. (d); ¹H NMR (DMSO-d₆) δ 2.35(s, 3H), 3.67 (d, 2H, J=6.0 Hz), 4.39 (m, 1H), ˜5.30 (bs, 1H), 7.45-7.48(m, 2H), 7.56 (d, 1H, J=8.8 Hz), 8.66 (s, 3H).

Example 1 Preparation of2-(3,5-dichloro-4-pyridinyl)-4-(4-bromophenyl)oxazoline (Compound 4)

N-(4-bromophenylglycine methyl ester)-3,5-dichloro-4-pyridinylcarboxamide

4-Bromophenylglycine methyl ester (36 mmol, 10.07 g) and3,5-dichloro-4-pyridinyl carbonyl chloride (40 mmol, 8.40 g) werecombined in 1,2-dichloroethane (200 mL) and pyridine (100 mmol, 8.09 mL)was added and the reaction stirred at ambient temperature for 18 hours.The reaction was washed with 1 M HCl and brine and dried over MgSO₄.Chromatography (SiO₂, EtOAc-Hex) afforded the product as a yellow oil(5.78 g).N-1-(4-bromophenyl)-2-hydroxyethyl-(3,5-dichloro-4-pyridinyl)carboxamide

N-(4-Bromophenylglycine methyl ester)-3,5-dichloro-4-pyridinylcarboxamide (13.5 mmol, 5.65 g), sodium borohydride (54.0 mmol, 2.04 g),and calcium chloride (27.0 mmol, 3.0 g) were combined in THF (20 mL) andethanol (40 mL) and stirred at ambient temperature for 36 hours. Theyellow suspension was poured into 1 M Sodium Acetate (100 ml) andstirred 20-30 min. before extracting with EtOAc. The organic extract waswashed with brine and dried over MgSO₄. Filtration and concentration invacuo afforded a yellow solid (5.24 g). Chromatography (SiO2, EtOAc)afforded the product as a white solid. (2.44 g, 57.5% yield): mp152-155° C.2-(3,5-dichloro-4-pyridinyl)-4-(4-bromophenyl)oxazoline (Compound 4)

To a suspension ofN-1-(4-bromophenyl)-2-hydroxyethyl-(3,5-dichloro-4-pyridinyl)carboxamide(5.84 mmol, 2.27 g) in 1,2-dichloroethane (80 mL) was added(diethylamino)sulfur trifluoride (DAST, 6.42 mmol, 0.85 mL) at −78° C.The reaction was allowed to warm slowly to room temperature and wasstirred for 18 hours. The reaction upon completion was poured into icecontaining NH₄OH (6 mL) and allowed to warm to ambient temperaturebefore extracting into methylene chloride. The organic extract waswashed with brine, dried over MgSO₄ and concentrated to an oil (2.60 g).Chromatography (SiO₂, 25% EtOAc-Hex) afforded the product as a whitesolid (1.63 g, 75% yield): mp 102-103° C.

Example 2 Preparation of2-(3,5-dichloro-4-pyridinyl)-4-(4-iodophenyl)oxazoline (Compound 11)

N-1-(4-iodophenyl)-2-hydroxyethyl-(3,5-dichloro-4-pyridinyl)carboxamide

A 250 mL round bottom flask equipped with a stir bar, thermocouple, anda reflux condenser was charged with4-[(1-amino)-(2-hydroxy)ethyl]-iodobenzene (HCl salt) (5.26 g, 17.6mmol), triethylamine (4.3 g, 5.7 mL, 42.2 mmol) and THF (25 mL). Thereaction mixture was cooled to 10° C. The 3,5-dichloro-4-pyridinylcarbonyl chloride (7.7 g, 17.6 mmol) was added to the THF solutionkeeping the temperature <30° C. The mixture was stirred at 25-30° C. for2 hours. Dichloromethane (100 mL) and water (100 mL) were added and thephases were separated. The aqueous phase was extracted withdichloromethane (2×50 mL). The combined organic phases were washed withaq. 0.5 N HCl (50 mL) and brine (50 mL). The dichloromethane was driedover sodium sulfate, filtered, and the solvents removed under reducedpressure to give product as a tan solid (7.4 g, 96%): mp 177-180° C.2-(3,5-dichloro-4-pyridinyl)-4-(4-iodophenyl)oxazoline (Compound 11)

A 50 mL round bottom flask equipped with a stir bar, thermocouple, and areflux condenser was charged withN-1-(4-iodophenyl)-2-hydroxyethyl-(3,5-dichloro-4-pyridinyl)carboxamide(1.07 g, 2.45 mmol) and dichloromethane (25 mL). The reaction mixturewas cooled to −78° C. (Diethylamino)sulfur trifluoride (396 mg, 0.325mL, 2.45 mmol) was added to the dichloromethane solution keeping thetemperature <−70° C. Reaction was allowed to warm to 25° C. and wasstirred overnight. The reaction mixture was poured into 50 g icecontaining conc. ammonium hydroxide (5 mL). The phases were separatedand the aqueous phase was extracted with dichloromethane (2×50 mL). Thecombined organic phases were washed with brine (50 mL), dried oversodium sulfate and filtered, and the solvents were removed under reducedpressure to give crude product as a tan solid. Chromatography gave pure2-(3,5-dichloro-4-pyridinyl)-4-(4-iodophenyl)oxazoline as a tan solid(740 mg, 72%): mp 90-92° C.

Example 3 Preparation of2-(3,5-dichloro-4-pyridinyl)-4-(4-(4-ethoxyphenyl)phenyl)oxazoline(Compound 12)

A solution of 2-(3,5-dichloro-4-pyridinyl)-4-(4-iodophenyl)oxazoline(0.2 g, 0.48 mmol), p-ethoxybenzeneboronic acid (0.095 g, 0.57 mmol),sodium carbonate (0.076 g, 0.72 mmol),dichlorobis(triphenylphosphine)palladium(II) (0.025 g) andtri-o-tolylphosphine (0.020 g) was heated at reflux for 12 h under anatmosphere of nitrogen. After cooling, 1N HCl (15 mL) was added and themixture was extracted with diethyl ether (3×30 mL). The combined etherlayers were dried over sodium sulfate, filtered and concentrated invacuo. The residue was purified by chromatography (eluant,ether/hexane—1:1) to give the product as an off-white solid: mp 121-122°C.

The following compounds were prepared according to the procedure ofExample 3.

Isolated as a white solid (62% yield): mp 144-146° C.; ¹H NMR (300 MHz,CDCl₃) δ 8.64 (s, 2H), 7.72 (s, 4H), 7.68-7.64 (Ar-m, 2H), 7.54-7.51(Ar-m, 2H), 5.62 (dd, 1H, J=8.6, 10.2 Hz), 4.97 (dd, 1H, J=8.5, 10.4Hz), 4.43(dd, 1H, J=8.5, 8.5 Hz); EI/MS 437 m/e (M⁺); Anal. Calcd. forC₂₁H₁₃Cl₂F₃N₂O₁: C, 57.69; H, 3.00; N, 6.41. Found: C, 57.64; H, 3.02;N, 6.33.

Isolated as a white solid (20% yield): mp 113-115° C.; ¹H NMR (300 MHz,CDCl₃) δ 8.61 (s, 2H), 7.61-7.58 (Ar-m, 4H), 7.48 (d, 2H, J=8.4 Hz),7.29 (d, 2H, J=7.7 Hz), 5.58 (dd, 1H, J=8.8, 10.2 Hz), 4.94 (dd, 1H,J=8.6, 10.2 Hz), 4.41 (dd, 1H, J=8.6, 8.6 Hz); EI/MS 352 m/e (M⁺); Anal.Calcd. for C₂₁H₁₃Cl₂F₃N₂O₂: C, 55.65; H, 2.89; N, 6.18. Found: C, 55.24;H, 2.82; N, 6.09.

Isolated as a white solid (34% yield): mp 145-147° C.; ¹H NMR (300 MHz,CDCl₃) δ 8.61 (s, 2H), 8.39 (d, 1H, J=2.6 Hz), 7.58-7.55 (d, 2H, J=8.4Hz), 7.47 (d, 2H, J=8.4 Hz), 6.82 (d, 1H, J=8.8 Hz), 5.58 (dd, 1H,J=8.6, 10.2 Hz), 4.94 (dd, 1H, J=8.4, 10.2 Hz), 4.40 (dd, 1H, J=8.6, 8.6Hz), 3.98 (s, 3H); EI/MS 400 m/e (M⁺).

Isolated as a tan solid (63% yield): mp 112-115° C.; ¹H NMR (300 MHz,CDCl₃) δ 8.60 (s, 2H), 7.61 (d, J=8.4 Hz, 2H), 7.44 (d, J=8.4 Hz, 2H),7.37-7.32 (m, 2H), 7.20 (d, J=8.1 Hz, 1H), 5.56 (dd, J=8.8, 10.2 Hz,1H), 4.92 (dd, J=8.8, 10.4 Hz, 1H), 4.41 (dd, J=8.8, 8.8 Hz, 1H), 2.33(s, 3H), 2.31 (s, 3H); EI/MS 397 m/e (M⁺).

Isolated as a tan solid (2% yield): mp 107-120° C.; ¹H NMR (300 MHz,CDCl₃) δ 8.61 (s, 2H), 7.63 (d, J=2.2 Hz, 2H), 7.62-7.44 (m, 4H), 7.26(d, J=7.6 Hz, 2H), 5.57 (dd, J=8.7, 10.2 Hz, 1H), 4.93 (dd, J=8.4, 10.2Hz, 1H), 4.41 (dd, J=8.7, 8.4 Hz, 1H), 2.40 (s, 3H); EI/MS 382 m/e (M⁺).

Isolated as a white solid (19% yield): mp 128-136° C.; ¹H NMR (300 MHz,CDCl₃) δ 8.61 (s, 2H), 7.57 (d, J=8.4 Hz, 2H), 7.37 (d, J=8.4 Hz, 2H),7.12 (d, J=3.6 Hz, 1H), 6.74 (dd, J=1.0, 3.6 Hz, 1H), 5.53 (dd, J=8.7,10.2 Hz, 1H), 4.91 (dd, J=8.4, 10.2 Hz, 1H), 4.37 (dd, J=8.4, 8.4 Hz,1H), 2.51 (s, 3H); EI/MS 388 m/e (M⁺).

33% yield, mp 109-110° C.; ¹H NMR (CDCl₃) δ 4.33 (t, 1H, J=2.8 Hz), 4.84(dd, 1H, J=2.8 Hz), 5.48 (dd, 1H, J=3.5 Hz), 5.92 (s, 2H), 6.80 (d, 2H,J=2.2 Hz), 6.98 (d, 2H, J=2.2 Hz), 7.35 (d, 2H, J=2.2 Hz), 7.45 (d, 2H,J=2.2 Hz), 8.53 (s, 2H); MS m/e 412 (M⁺).

Isolated as a yellow solid (53% yield): mp 130° C.; ¹H NMR (300 MHz,CDCl₃) δ 8.61 (s, 2H), 7.55 (d, 2H), 7.48 (d, 2H), 7.42-7.17 (m, 3H),5.58 (dd, 1H), 4.94 (dd, 1H), 4.39 (dd, 1H); EI/MS 404 m/e (M⁺).

15% yield as a clear oil: ¹H NMR (300 MHz, CDCl₃) δ 8.62 (s, 2H),7.84-7.49 (m, 8H), 5.60 (dd, 1H), 4.95 (dd, 1H), 4.41 (dd, 1H); EI/MS437 m/e (M⁺).

20% yield as an orange solid: mp 153-157° C.; ¹H NMR (300 MHz, CDCl₃) δ8.61 (s, 2H), 7.60-7.39 (m, 8H), 5.58 (dd, 1H), 4.94 (dd, 1H), 4.40 (dd,1H); EI/MS 404 m/e (M⁺).

Isolated as a brown gum (74% yield): ¹H NMR (300 MHz, CDCl₃) δ 8.62 (s,2H), 7.75 (s, 1H), 7.57 (d, 1H), 7.49 (br, 5H), 5.60 (dd, 1H), 4.95 (dd,1H), 4.45 (dd, 1H); EI/MS 470 m/e (M⁺).

Isolated as a dark amber oil (20% yield): ¹H NMR (300 MHz, CDCl₃) δ 8.61(s, 2H), 7.49-7.28 (m, 8H), 5.59 (dd, 1H), 4.95 (dd, 1H), 4.45 (dd, 1H);EI/MS 404 m/e (M⁺).

Isolated as an orange solid (80% yield): mp 98-103° C.; ¹H NMR (300 MHz,CDCl₃) δ 8.61 (s, 2H), 7.61 (d, J=8.42 Hz, 2H), 7.48 (d, J=8.06 Hz, 2H),7.42-7.36 (m, 2H), 7.31-7.27 (m, 1H), 7.07-7.02 (m, 1H), 5.58 (dd,J=9.52, 9.89 Hz, 1H), 4.94 (dd, J=10.25, 8.42 Hz, 1H), 4.41 (dd, J=8.42,8.42 Hz, 1H); EI/MS 387 m/e (M⁺).

Isolated as an amber oil (63% yield): ¹H NMR (300 MHz, CDCl₃) δ 8.61 (s,2H), 7.62-7.33 (m, 8H), 5.58 (dd, 1H), 4.94 (dd, 1H), 4.40 (dd, 1H);EI/MS 404 m/e (M⁺).

Isolated as a light brown solid (27% yield): mp 146-149° C.; ¹H NMR (300MHz, CDCl₃) δ 8.61 (s, 2H), 7.59-7.52 (m, 4H), 7.46 (d, J=8.42 Hz, 2H),7.16-7.10 (m, 2H), 5.57 (dd, J=10.25, 8.79 Hz, 1H), 4.93 (dd, J=10.44,8.79 Hz, 1H), 4.40 (dd, J=8.61, 8.79 Hz, 1H); EI/MS 386 m/e (M⁺).

Isolated as a light tan solid (80% yield): mp 97-98° C.; ¹H NMR (300MHz, CDCl₃) δ 8.61 (s, 2H), 7.75 (d, J=7.69 Hz, 1H), 7.56 (t, J=7.42 Hz,1H), 7.49-7.42 (m, 4H), 7.37-7.30 (m, 2H), 5.58 (dd, J=9.61, 10.16 Hz,1H), 4.95 (dd, J=10.16, 8.52 Hz, 1H), 4.45 (dd, J=8.79, 8.79 Hz, 1H),EI/MS 436 m/e (M⁺).

Isolated as a light orange solid (92% yield): mp 91-93° C.; ¹H NMR (300MHz, CDCl₃) δ 8.61 (s, 2H), 7.61-7.58 (m, 2H), 7.49-7.41 (m, 2H),7.36-7.29 (m, 2H), 7.24-7.12 (m 2H), 5.59 (dd, J=10.25, 8.79 Hz, 11H),4.94 (dd, J=10.25, 8.42 Hz, 1H), 4.42 (dd, J=8.61, 8.42 Hz, 1H); EI/MS386 m/e (M⁺).

Isolated as an orange foam (93% yield): ¹H NMR (300 MHz, CDCl₃) δ 8.62(s, 2H), 8.02 (broad m, 4H), 7.86 (broad m, 1H), 7.68-7.64 (m, 2H),7.56-7.53 (m, 2H), 5.62 (dd, J=10.25, 8.79 Hz, 1H); 4.96 (dd, J=10.44,8.79 Hz, 1H), 4.40 (dd, J=8.62, 8.79 Hz, 1H); EI/MS 504 m/e (M⁺).

Isolated as an off-white solid (34% yield): mp 78-81° C.; ¹H NMR (300MHz, CDCl₃) δ 8.61 (s, 2H), 7.44 (d, J=8.0 Hz, 2H), 7.37 (d, J=8.0 Hz,2H), 7.28-7.21 (m, 4H), 5.58 (dd, J=9.1, 10.2 Hz, 1H), 4.95 (dd, J=8.6,10.4 Hz, 1H), 4.45 (t, J=8.6 Hz, 1H), 2.28 (s, 3H); EI/MS 382 m/e (M⁺);Anal. Calcd. for C₂₁H₁₆Cl₂N₂O: C, 65.81; H, 4.21; N, 7.31. Found: C,65.67; H, 4.26; N, 7.36.

Isolated as a brown solid (30% yield): mp 88-91° C.; ¹H NMR (300 MHz,CDCl₃) δ 8.61 (s, 2H), 7.59 (d, 2H), 7.46 (d, 2H), 7.29-7.22 (m, 3H),5.57 (dd, 1H), 4.93 (dd, 1H), 4.40 (dd, 1H), 2.31 (d, 3H); EI/MS 400 m/e(M⁺).

Isolated as an off-white solid (33% yield): mp 84-87° C.; ¹H NMR (300MHz, CDCl₃) δ 8.61 (s, 2H), 7.62 (d, J=8.4 Hz, 2H), 7.46 (d, J=8.0 Hz,2H), 7.41-7.31 (m, 3H), 7.17 (d, J=7.3 Hz, 1H), 5.58 (dd, J=8.7, 10.2Hz, 1H), 4.94 (dd, J=8.4, 10.2 Hz, 1H), 4.42 (dd, J=8.4, 8.7 Hz, 1H),2.43 (s, 3H); EI/MS 382 m/e (M⁺).

Isolated as a brown solid (53% yield): mp 141-143° C.; ¹H NMR (300 MHz,CDCl₃) δ 8.61 (s, 2H), 7.62 (dd, J=7.3, 9.5 Hz, 4H), 7.49-7.36 (m, 5H),5.59 (dd, J=8.7, 10.2 Hz, 1H), 4.94 (dd, J=8.4, 10.2 Hz, 1H), 4.42 (dd,J=8.4, 8.7 Hz, 1H); EI/MS 368 m/e (M⁺).

Isolated as a yellow oil (48% yield): ¹H NMR (300 MHz, CDCl₃) δ 8.61 (s,2H), 7.63-7.49 (m, 6H), 7.32 (m, 1H), 5.60 (dd, J=8.8, 10.4 Hz, 1H),4.95 (dd, J=8.8, 10.4 Hz, 1H), 4.42 (dd, J=8.8, 8.8 Hz, 1H); EI/MS 455m/e (M⁺).

Isolated as a light yellow solid (21% yield): mp 123-128° C.; ¹H NMR(300 MHz, CDCl₃) δ 8.61 (s, 2H), 7.61 (d, J=8.0 Hz, 2H), 7.53 (d, J=8.0Hz, 2H), 7.46 (d, J=8.4 Hz, 2H), 7.31 (d, J=8.4 Hz, 2H), 5.57 (dd,J=8.7, 10.2 Hz, 1H), 4.93 (dd, J=8.4, 10.2 Hz, 1H), 4.40 (dd, J=8.4, 8.7Hz, 1H), 2.96 (h, J=6.9 Hz, 1H), 1.29 (d, J=6.9 Hz, 6H); EI/MS 410 m/e(M⁺).

Isolated as a white solid (71% yield): mp 98-99° C.; ¹H NMR (300 MHz,CDCl₃) δ 8.61 (s, 2H), 7.66-7.57 (m, 4H), 7.51 (d, 2H), 7.31 (t, 1H),5.60 (dd, 1H), 4.96 (dd, 1H), 4.42 (dd, 1H); EI/MS 454 m/e (M⁺).

26% yield as a yellow oil: ¹H NMR (300 MHz, CDCl₃) δ 8.61 (s, 2H),7.61-7.13 (m, 7H), 5.60 (dd, 1H), 4.96 (dd, 1H), 4.42 (dd, 1H); EI/MS455 m/e (M⁺).

67% yield as a yellow oil: ¹H NMR (300 MHz, CDCl₃) δ 8.60 (s, 2H), 7.56(d, 2H), 7.45 (d, 2H), 7.34-6.99 (m, 3H), 5.58 (dd, 1H), 4.94 (dd, 1H),4.41 (dd, 1H), 2.39 (s, 3H); EI/MS 400 m/e (M⁺).

Isolated as a yellow oil (85% yield): ¹H NMR (300 MHz, CDCl₃) δ 8.58 (s,2H), 7.68 (d, 1H), 7.55 (m, 3H), 7.48 (d, 2H), 7.22 (m, 1H), 5.55 (dd,1H), 4.90 (dd, 1H), 4.38 (dd, 1H); EI/MS 455 m/e (M⁺).

Isolated as a tan solid (83% yield): mp 170-173° C.; ¹H NMR (300 MHz,CDCl₃) δ 8.61 (s, 2H), 7.61 (d, J=8.4 Hz, 2H), 7.53 (d, J=8.4 Hz, 2H),7.46 (d, J=8.4 Hz, 2H), 7.33 (d, J=8.4 Hz, 2H), 5.51 (dd, J=8.4, 10.3Hz, 1H), 4.93 (dd, J=8.4, 10.3 Hz, 1H), 4.41 (dd, J=8.4, 8.4 Hz, 1H),2.53 (s, 3H); EI/MS 415 m/e (M⁺).

Isolated as a yellow solid (68% yield): mp 153-156° C.; ¹H NMR (300 MHz,CDCl₃) δ 8.61 (s, 2H), 7.73 (m, 4H), 7.65 (d, J=8.4 Hz, 2H), 7.50 (d,J=8.4 Hz, 2H), 5.60 (dd, J=8.8, 10.1 Hz, 1H), 4.95 (dd, J=8.8, 10.1 Hz,1H), 4.41 (dd, J=8.8, 8.8 Hz, 1H), 2.77 (s, 3H); EI/MS 431 m/e (M⁺).

Isolated as a tan solid (76% yield): mp 135-138° C.; ¹H NMR (300 MHz,CDCl₃) δ 8.61 (s, 2H), 7.61 (d, J=8.1 Hz, 2H), 7.57 (s, 4H), 7.48 (d,J=8.4 Hz, 2H), 5.76 (d, J_(H-F)=52.7 Hz, 2H), 5.58 (dd, J=8.4, 10.3 Hz,1H), 4.94 (dd, J=8.4, 10.3 Hz, 1H), 4.41 (dd, J=8.4, 8.4 Hz, 1H); EI/MS433 m/e (M⁺).

Example 4 Preparation of2-(3,5-difluoro-4-pyridinyl)-4-(4-iodophenyl)oxazoline (Compound 38)

The procedure of Example 2 was repeated using 3,5-difluoro-4-pyridinylcarbonyl chloride as the starting material. Product was isolated as anoff-white solid (1.52 g, 62%): mp 84-86° C.; ¹H NMR (CDCl₃) δ 8.49 (s,2H), 7.72 (d, 2H, J=8.4 Hz), 7.06 (d, 2H, J=8.4 Hz), 5.45 (dd, 1H,J=10.3, 8.8 Hz), 4.85 (dd, 1H, J=10.3, 8.4 Hz), 4.29 (dd, 1H, J=8.8, 8.4Hz); EI/MS 386 m/e (M⁺); For C₁₄H₉F₂N₂O; Calculated: C, 43.55; H, 2.35;N, 7.25; Found: C, 43.46; H, 2.40; N, 7.17.

Example 5 Preparation of2-(3,5-difluoro-4-pyridinyl)-4-(4-(4-trifluoromethylphenyl)phenyl)-oxazoline(Compound 39)

The procedure of Example 3 was repeated using the appropriate startingmaterials and the product was isolated as a tan solid (73% yield): mp136-138° C.; ¹H NMR (300 MHz, CDCl₃) δ 8.50 (s, 2H), 7.69 (s, 4H), 7.62(d, J=8.4 Hz, 2H), 7.43 (d, J=8.4 Hz, 2H), 5.56 (dd, J=8.4, 10.1 Hz,1H), 4.92 (dd, J=8.4, 10.1 Hz, 1H), 4.39 (dd, J=8.4, 8.4 Hz, 1H); EI/MS404 m/e (M⁺).

The following compound was similarly prepared according to the procedureof Example 3.

Isolated as an orange solid (55% yield): mp 92-95° C.; ¹H NMR (300 MHz,CDCl₃) δ 8.50 (s, 2H), 7.60-7.57 (m, 4H), 7.40 (d, J=8.1 Hz, 2H), 7.28(d, J=8.1 Hz, 2H), 5.55 (dd, J=8.4, 10.2 Hz, 1H), 4.89 (dd, J=8.4, 10.2Hz, 1H), 4.38 (dd, J=8.4, 8.4 Hz, 1H); EI/MS 420 m/e (M⁺).

Example 6 Preparation of4-[4-(4-bromo-2-methylphenyl)4,5-dihydro-1,3-oxazol-2-yl]-3,5-dichloropyridine(Compound 41)

N-[1-(4-bromo-2-methylphenyl)-2-hydroxyethyl]-3,5-dichloroisonicotinamide

To a suspension of 1-(4-bromo-2-methylphenyl)-2-hydroxyethanaminiumchloride_(3.0 g, 11.2 mmol) in THF (100 mL) was added dropwisetriethylamine (2.85 g, 28.1 mmol) at 0° C. To the resulting white slurrywas added dropwise a solution of 3,5-dichloroisonicotinoyl chloride,freshly prepared from lithium 3,5-dichloroisonicotinate (2.34 g, 11.8mmol), and the resulting tan slurry was warmed to room temperature andstirred for 16 h. The reaction was diluted with water and the THF wasremoved in vacuo. The aqueous residue was extracted with CH₂Cl₂ (2×100mL), and the organic extracts were combined, washed with 2 N HCl, washedwith brine, dried (Na₂SO₄), filtered, and the CH₂Cl₂ removed in vacuo togive the crude product as an oily, brown solid. Trituration with Et₂Oafforded the desired product (3.0 g, 67%) as a tan solid: mp 192-194°C.; ¹H NMR (DMSO-d₆) δ 2.45 (s, 3H), 3.88-3.97 (m, 2H), 5.40-5.46 (m,1H), 6.66 (d, 1H, J=7.0 Hz), 7.21-7.39 (m, 3H), 8.50 (s, 2H); EI/MS 404m/e (M⁺).4-[4-(4-bromo-2-methylphenyl)-4,5-dihydro-1,3-oxazol-2-yl]-3,5-dichloropyridine(Compound 41)

To a suspension ofN-[1-(4-bromo-2-methylphenyl)-2-hydroxyethyl]-3,5-dichloroisonicotinamide(2.90 g, 7.2 mmol) in CH₂Cl₂ (75 mL) was added dropwise(diethylamino)sulfur trifluoride (1.16 g, 7.2 mmol) at −78° C. Thecooling bath was removed and the light orange mixture was warmed to roomtemperature. The resulting light orange solution was stirred at roomtemperature for 16 h. The reaction mixture was poured into 100 g of icecontaining conc. NH₄OH (25 mL). The phases were separated and theaqueous phase was extracted with CH₂Cl₂ (2×50 mL). The organic extractswere combined, washed with brine, dried (Na₂SO₄), filtered, and thesolvents removed in vacuo to give crude product as a tan solid. Flashchromatography (SiO₂; 20% EtOAc/hexanes) afforded pure product as awhite solid (2.25 g, 81%): mp 93-95° C.; ¹H NMR (CDCl₃) δ 2.32 (s, 3H),4.17 (dd, 1H, J=8.7, 8.7 Hz), 4.94 (dd, 1H, J=8.4, 10.4 Hz), 5.65 (dd,1H, J=9.7, 9.7 Hz), 7.32-7.39 (m, 3H), 8.60 (s, 2H); EI/MS 386 m/e (M⁺);Anal. Calcd. for C₁₅H₁₁BrCl₂N₂O: C, 46.67; H, 2.87; N, 7.26. Found: C,46.85; H, 2.77; N, 7.19.

Example 7 Preparation of2-(3,5-dichloro-4-pyridinyl)-4-(4-(4-trifluoromethylphenyl)-2-methylphenyl)-oxazoline(Compound 43)

To a solution of4-[4-(4-bromo-2-methylphenyl)-4,5-dihydro-1,3-oxazol-2-yl]-3,5-dichloropyridine(0.5 g, 1.3 mmol) in EtOH (13 mL) was added K₂CO₃ (0.27 g, 2.0 mmol) and4-(trifluoromethyl)benzeneboronic acid (0.25 g, 1.3 mmol). The mixturewas degassed prior to the addition of (PPh₃)₄Pd(0) (3-10 mol %), andthen stirred at reflux for 16 h. Additional boronic acid was added andthe mixture was stirred at reflux for 3 h. The reaction was cooled toroom temperature and stirred for 48 h. The reaction was diluted withCH₂Cl₂ (100 mL), washed with 2 N HCl, and the aqueous was extracted withadditional CH₂Cl₂. The organic extracts were combined, washed withbrine, dried (Na₂SO₄) and filtered, and the solvent was removed in vacuoto give the crude product as a light yellow oil. Flash chromatography(SiO₂; 0-20% Et₂O/hexanes) afforded a colorless oil. The oil wasdissolved in hot hexane and then cooled in the freezer. Vacuumfiltration afforded the product (0.2 g, 34%) as a white crystallinesolid: mp 129-131° C.; ¹H NMR (CDCl₃) δ 2.46 (s, 3H), 4.28 (dd, 1H,J=8.2, 9.0 Hz), 5.01 (dd, 1H, J=8.2, 10.4 Hz), 5.78 (dd, 1H, J=9.0, 10.4Hz), 7.45 (d, 1H, J=1.8 Hz), 7.51 (dd, 1H, J=1.8, 8.0 Hz), 7.59 (d, 1H,J=8.0 Hz), 7.70 (s, 4H), 8.63 (s, 2H); Anal. Calcd. for C₂₂H₁₅Cl₂F₃N₂O:C, 58.55; H, 3.35; N, 6.21. Found: C, 58.54; H, 3.35; N, 6.17.

The following compound was similarly prepared according to the procedureof Example 7.

Isolated as a white solid (43% yield): mp 127-129° C.; ¹H NMR (CDCl₃) δ1.45 (t, 3H, J=7.0 Hz), 2.43 (s, 3H), 4.08 (q, 2H, J=7.0 Hz), 4.28 (dd,1H, J=8.6, 8.6 Hz), 4.98 (dd, 1H, J=8.2, 10.4 Hz), 5.65 (dd, 1H, J=9.2,10.2 Hz), 6.96 (d, 2H, J=8.8 Hz), 7.40-7.47 (m, 3H), 7.51 (d, 2H, J=8.8Hz), 8.62 (s, 2H); EI/MS 427 m/e (M⁺); Anal. Calcd. for C₂₃H₂₀Cl₂N₂O: C,64.65; H, 4.72; N, 6.65. Found: C, 64.31; H, 4.76; N, 6.49.

Example 8 Preparation of2-(3,5-dichloro-4-pyridinyl)-4-(4-(4-trifluoromethoxyphenyl)-2-methylphenyl)-oxazoline(Compound 44)

To a mixture of4-[4-(4-bromo-2-methylphenyl)-4,5-dihydro-1,3-oxazol-2-yl]-3,5-dichloropyridine(0.46 g, 1.2 mmol), 4-(trifluoromethoxy)benzeneboronic acid (0.26 g, 1.2mmol), NA₂CO₃ (0.18 g, 1.7 mmol), and tri-o-tolylphosphine (0.07 g, 0.2mmol) in 10% H₂O/CH₃CN (13.2 mL) was added (PPh₃)₂PdCl₂ (0.08 g, 0.1mmol) and the resulting amber mixture was stirred at reflux for 16 h.The black mixture was cooled to room temperature, diluted with 2N HCl,and the acetonitrile was removed in vacuo. The aqueous residue wasextracted with CH₂Cl₂(2×150 mL), and the organic extracts were combined,washed with brine, dried (Na₂SO₄) and filtered, and the solvent wasremoved in vacuo to give the crude product as an orange oil. Flashchromatography (SiO₂; 0-30% Et₂O/hexanes) afforded a colorless oil. Theoil was dissolved in hot hexane and then cooled in the freezer. Vacuumfiltration afforded the target compound (0.16 g, 28%) as a white solid:mp 100-102° C.; ¹H NMR (CDCl₃) δ 2.44 (s, 3H), 4.27 (dd, 1H, J=8.6, 8.6Hz), 5.00 (dd, 1H, J=8.2, 10.4 Hz), 5.77 (dd, 1H, J=10.2, 9.2 Hz), 7.27(d, 2H, J=10.2 Hz), 7.40 (s, 1H), 7.45 (dd, 1H, J=1.8, 9.0 Hz), 7.54 (s,1H), 7.60 (d, 2H, J=8.8 Hz), 8.62 (s, 2H); EI/MS 467 m/e (M⁺); Anal.Calcd. for C₂₂H₁₅Cl₂F₃N₂O₂: C, 56.55; H, 3.24; N, 6.00. Found: C, 56.44;H, 3.37; N 5.90.

Example 9 Preparation of4-[4-(4′-Iodophenyl)-5-methyl-4,5-dihydro-oxazol-2-yl]-3,5-dichloropyridines(Compounds 45 & 46)

N-[2-Hydroxy-1-(4-iodophenyl)-propyl]-2,5-dichloroisonicotinamide

Lithium-3,5-dichloropyridine-4-carboxylate (0.54 g, 2.7 mmol) wassuspended in 1,2-dichloroethane (10 mL). Thionyl chloride (0.42 mL, 5.7mmol) and dimethylformamide (3 drops from a Pasteur pipette) were added.After refluxing under nitrogen for 5.5 hours, the reaction mixture wascooled to room temperature and concentrated under reduced pressure.1,2-Dichloroethane (20 mL) was added to the residue and re-concentratedunder reduced pressure. The brown residue was taken up in drytetrahydrofuran (2.5 mL) and added to a suspension of1-amino-2-hydroxy-1-(4-iodophenyl)propane hydrochloride (0.85 g, 2.7mmol) in dry tetrahydrofuran (5 mL) at −5° C. The addition rate wascontrolled to keep reaction temperature at 0° C. The reaction mixturewas stirred at room temperature for 14 hours. Methylene chloride (20 mL)and water (20 mL) were added to the reaction mixture and the organiclayer was collected. The aqueous layer was extracted with more methylenechloride (2×10 mL). Combined organic extracts were washed with water (50mL) and brine (30 mL), dried over magnesium sulfate, adsorbed on tosilica, applied to a Michel-Miller column and eluted with 2:1hexane/ethyl acetate. The major fraction was collected and concentratedunder reduced pressure to leave 0.94 g (76%) of white solid: mp 210-213°C.; ¹H NMR (DMSO-d₆) δ 9.32 (dd, 1H)*, 8.68 (s, 2H), 7.68 (d, 2H), 7.19(dd, 2H), 4.71-4.95 (m, 2H)**, 3.91 & 3.80 (m, 1H), 1.13 (m, 3H).MI=451. IR (KBr) cm⁻¹ 3282 & 1654.

* Signal disappeared upon shaking with D₂O

** Signal collapsed into 2 doublets integrating to 1H upon D₂O shake4-[4-(4′-Iodophenyl)-5-methyl-4,5-dihydro-oxazol-2-yl]-3,5-dichloropyridines(Compounds 45 & 46)

N-[2-Hydroxy-1-(4-iodophenyl)-propyl]-2,5-dichloroisonicotinamide (918mg, 2 mmol) was dissolved in methylene chloride (220 mL) and cooled to−78° C. To this cloudy suspension was added (diethylamino)sulphurtrifluoride (0.33 g, 2 mmol) at a dropwise rate over 10 minutes. Thereaction mixture was allowed to come to room temperature overnight andpoured into crushed ice (80 g) containing ammonia solution (10 mL). Theorganic layer was collected and the aqueous layer was extracted withmethylene chloride (2×50 mL). Combined organic layers were washed withwater (150 mL) and brine (100 mL), dried over magnesium sulfate,adsorbed onto silica, applied to a Michel-Miller column and eluted with,a gradient of ethyl acetate in hexane. Two pure fractions and onefraction containing a mixture of both compounds were collected andconcentrated under reduced pressure. The faster moving fraction wasshown by ¹H NMR to contain the anti diastereomers. ¹H NMR (CDCl₃) δ 8.60(s, 2H), 7.73 (d, 2H), 7.12 (d, 2H), 4.92 (d, 2H), 4.67 (p, 1H), 1.61(d, 3H); MI=433; mp 117-119° C. The total yield of this material wasestimated by NMR to be 0.11 g (12%). The slower moving fraction wasshown by ¹H NMR to contain the syn diastereomers. ¹H NMR (CDCl₃) δ 8.60(s, 2H), 7.71 (d, 2H), 7.12 (d, 2H), 5.56 (d, 1H), 5.19-5.30 (m, 1H),0.99 (t, 1H); MI=432; mp 99-100° C. The yield of this material wasestimated by NMR to be 0.28 g (27%).

Example 10 Preparation of4-[5-Methyl-4-(4′-trifluoromethoxybiphenyl)-4-yl)-4,5-dihydro-oxazol-2-yl]-3,5-dichloropyridines(Compounds 47 & 48)

4-[4-(4′-Iodophenyl)-5-methyl-4,5-dihydro-oxazol-2-yl]-3,5-dichloropyridines(50/50 mixture, 200 mg, 0.5 mmol), 4-(trifluoromethoxy)-benzeneboronicacid (95 mg, 0.5 mmol), sodium carbonate (88 mg, 0.8 mmol),tri-o-tolylphosphine (14 mg, 45 nmol) anddichlorobis(triphenylphosphine)-palladium(II) (32 mg, 45 nmol) werecombined in acetonitrile (5 mL). Water (0.5 mL) was added and themixture refluxed under nitrogen for 5 hours. After cooling to roomtemperature, the mixture was poured into dilute hydrochloric acid (1N,12 mL) and extracted with ether (3×15 mL). Combined ethereal extractswere washed with water (70 mL) and brine (70 mL), dried over magnesiumsulphate, adsorbed onto silica, applied to a Michel-Miller column andeluted with 10:1 hexane/ethyl acetate. Two fractions were collected andconcentrated under reduced pressure. The faster moving fraction wasshown by ¹H NMR to contain the anti diastereomers. ¹H NMR (CDCl₃) δ 8.61(s, 2H), 7.61 (d, 2H), 7.58 (d, 2H), 7.46 (d, 2H), 7.28 (d, 2H), 5.02(d, 2H), 4.77 (p, 1H), 1.65 (d, 3H); MI=466; mp 132-133° C.; Yield ofbrown powder 34 mg (31%). The slower moving fraction was shown by ¹H NMRto contain the syn diastereomers. ¹H NMR (CDCl₃) δ 8.61 (s, 2H), 7.61(d, 2H), 7.57 (d, 2H), 7.42 (d, 2H), 7.28 (d, 2H), 5.66 (d, 1H), 5.29(m, 1H), 1.05 (d, 3H); MI=466; mp=147-148° C.; Yield of white powder 36mg (33%).

Phytologically acceptable acid addition salts of the compounds offormula (I) are also within the scope of the invention. For example,boron tetrafluoride, hydrogen chloride, hydrogen bromide, hydrogeniodide, hydrogen sulfate, or organic acid salts may be used.

The compounds identified in the following Tables were prepared using theprocedures illustrated in the foregoing examples, and the compounds weretested against tobacco budworm (TBW), beet armyworm (BAW), cabbagelooper (CL), cotton aphid (CA), two-spotted spider mite (SM), andsweetpotato whitefly (WF) using procedures described hereinafter.

TABLE 1

compound number R mp ° C. TBW BAW CL CA SM WF  1 —H oil — — — F G F  2—Cl oil G G G A F F  3 —F 93-95 G G G B G B  4 —Br 102-103 G G G A A — 5

144-146 F A A B A F  6

113-115 G A A A A F  7

145-147 G D B G A —  8

112-115 G A B B — —  9

107-110 G A G A G G 10

128-136 G B A D G G 11 —I 90-92 G G G A A A 12

121-122 B A D B A B 13

109-110 G D A B F G 14

130 G B G D A G 15

oil G A A F F G 16

153-157 D A A F A G 17

gum G A A D A F 18

oil G G B E F G 19

98-103 G G D F A F 20

oil G G A F G G 21

146-149 G B G A A F 22

97-98 G G G C G G 23

91-93 G D A A A G 24

foam G A G F G F 25

78-81 G A F B G G 26

88-91 G D D D G G 27

84-87 F A A A B G 28

141-143 G B G F A G 29

oil B B A F C G 30

123-128 G A D F C F 31

98-99 D G G G F G 32

oil A A G C A A 33

oil G B G F G G 34

oil G D A B G G 35

170-173 G A A F G G 36

153-156 D G A F G F 37

135-138 G G D A F G

TABLE 2

compound number R mp ° C. TBW BAW CL CA SM WF 38 —I 84-86 G C G F A A 39

136-138 G B A F A F 40

92-95 G A A F A G

TABLE 3

compound number R mp ° C. TBW BAW CL CA SM WF 41 —Br 93-95 G G G A F F42

127-129 G A B B A G 43

129-131 A A A B B F 44

100-102 A A A B A E

TABLE 4 Compound #45

Compound #46

Compound #47

Compound #48

compound number mp ° C. TBW BAW CL CA SM WF 45  99-100 A 46 117-119 G GG F F G 47 147-148 A A A A A G 48 132-133 A G A B E F TBW refers toactivity at 400 ppm against tobacco budworm, BAW refers to activity at400 ppm against beet armyworm, CL refers to activity at 400 ppm againstcabbage looper, CA refers to activity at 50 ppm against cotton aphid, SMrefers to activity at 2.5 ppm against two-spotted spider mite, WF refersto activity at 200 ppm against whitefly,In each case the rating scale is as follows

% Control Rating 90-100 A 80-89 B 70-79 C 60-69 D 50-59 E less than 50 FInactive GInsecticide and Miticide Utility

The compounds of the invention are useful for the control of insects,mites, and aphids. Therefore, the present invention also is directed toa method for inhibiting an insect, mite, or aphid which comprisesapplying to a locus of the insect or mite an insect- or mite-inhibitingamount of a compound of formula (I).

The compounds are useful for reducing populations of insects and mitesand are useful in a method of inhibiting an insect or mite populationwhich comprises applying to a locus of the insect or mite an effectiveinsect- or mite-inactivating amount of a compound of formula (I). The“locus” of insects or mites is a term used herein to refer to theenvironment in which the insects or mites live or where their eggs arepresent, including the air surrounding them, the food they eat, orobjects which they contact. For example, plant-ingesting insects ormites can be controlled by applying the active compound to plant partsthat the insects or mites eat, particularly the foliage. It iscontemplated that the compounds might also be useful to protecttextiles, paper, stored grain, or seeds by applying an active compoundto such substance. The term “inhibiting an insect or mite” refers to adecrease in the numbers of living insects or mites, or a decrease in thenumber of viable insect or mite eggs. The extent of reductionaccomplished by a compound depends, of course, upon the application rateof the compound, the particular compound used, and the target insect ormite species. At least an inactivating amount should be used. The terms“insect-inactivating amount” and “mite-inactivating amount” are used todescribe the amount, which is sufficient to cause a measurable reductionin the treated insect or mite, population. Generally an amount in therange from about 1 to about 1000 ppm by weight active compound is used.

In a preferred embodiment, the present invention is directed to a methodfor inhibiting a mite or aphid which comprises applying to a plant aneffective mite- or aphid-inactivating amount of a compound of formula(I).

Insecticidal Test for Tobacco Budworm (Heliothis virescens), BeetArmyworm (Spodoptera exigua), and Cabbage Looper (Trichoplusia ni).

To prepare the test solution, the test compound was formulated at 400ppm in 7.5 mL of 2 acetone:1 tap water. 250 μL of the test solution waspipetted upon the surface of 8 mL of lepidopteran diet (modified Shorey)contained in each of five one-ounce plastic cups (one cup=1replication). A second-instar beet armyworm was placed upon the treateddiet in each cup once the solvent had air-dried. The solutions remainingafter completing applications to the one-ounce cups were then used asleaf-dip solutions for 3.5 cm leaf discs cut from cabbage leaves andcotton cotyledons. Five discs of each type of plant were dipped untilthoroughly coated into each rate of each compound (=5 replications ofeach treatment). After air-drying, the treated leaf discs were placedindividually into one-ounce plastic cups. Each dried, treated cottoncotyledon disc was infested with a 2^(nd) instar tobacco budworm larva,and each cabbage leaf disc was infested with a 2^(nd) instar cabbagelooper larva. Cups containing the treated substrates and larvae werecapped and then held in a growth chamber at 25° C., 50-55% RH, and 14 hrlight: 10 hr dark for 5 days. The number of dead insects of 5 perspecies per treatment was then determined and the results are given inTables 1-4.

Insecticidal Test for Cotton Aphid (Aphis gossypii)

To prepare spray solutions, 1 mg of each test compound was dissolvedinto 1 mL of a 90:10 acetone:ethanol solvent. This 1 mL of chemicalsolution was added to 19 mL of water containing 0.05% Tween 20surfactant to produce a 50 ppm spray solution.

Squash cotyledons were infested with cotton aphid (all life stages)16-20hours prior to application of spray solution. The solution was sprayedon both sides of each infested squash cotyledon (0.5 mL×2 each side)with a sweeping action until runoff. The plants were allowed to air dryand held for 3 days in a controlled room at 26° C. and 40% RH afterwhich time the test was graded. Grading was by actual count using adissecting microscope and comparison of test counts to the untreatedcheck. Results are given in Tables 1-4 as percent control based onpopulation reduction versus the untreated.

Insecticidal Test for Two-Spotted Spider Mite (Tetranychus urticae)

Ovicide Method:

Ten adult female two-spotted spider mites were placed on eight 2.2 cmleaf discs of cotton leaf, allowed to oviposit over 24 hours, andthereafter removed. The leaf discs were sprayed with 100 ppm testsolutions using a hand syringe, then allowed to dry with sixteen discsleft untreated as a negative control. Discs were placed on an agarsubstrate and held at 24° C. and 90% RH for 6 days. Percent controlbased on the number of hatched larvae on treated discs and the number onuntreated discs is reported in Tables 1-4.

Insecticidal Test for Sweetpotato Whitefly (Bemisia tabacia)

Four mg of each test compound was dissolved by adding 4 mL of a 90:10acetone:ethanol solvent mixture to the vial containing the samplecompound. This solution was added to 16 mL of water containing 0.05%Tween 20 surfactant to produce 20 mL of a 200 ppm spray solution.

Five-week-old cotton plants reared in a greenhouse were stripped of allfoliage except for the two uppermost true leaves that were greater than5 cm in diameter.

These plants were then placed into a laboratory colony of whiteflies fortwo days for oviposition by the colony females. All whiteflies were thenremoved from the test plants with pressurized air. The spray solutionwas then applied to the test plants with a hand-held syringe fitted withhollow cone nozzle. One mL of spray solution was applied to each leaftop and bottom for a total of 4 mL per plant. Four replications of eachtest compound utilized a total of 16 mL spray solution. Plants were airdried and then placed in a holding chamber (28° C. and 60% RH) for 13days. Compound efficacy was evaluated by counting, under an illuminatedmagnifying glass, the number of large nymphs (3rd-4th instar) per leaf.

Percent control based on reduction of large nymphs of a test compoundcompared to solution-only (no test compound) sprayed plants is reportedin Tables 1-4.

In addition to being effective against mites, aphids, and insects whenapplied to foliage, compounds of formula (I) have systemic activity.Accordingly, another aspect of the invention is a method of protecting aplant from insects which comprises treating plant seed prior to plantingit, treating soil where plant seed is to be planted, or treating soil atthe roots of a plant after it is planted, with an effective amount of acompound of formula (I).

Compositions

The compounds of this invention are applied in the form of compositionswhich are important embodiments of the invention, and which comprise acompound of this invention and a phytologically-acceptable inertcarrier. The compositions are either concentrated formulations that aredispersed in water for application, or are dust or granular formulationsthat are applied without further treatment. The compositions areprepared according to procedures and formulae which are conventional inthe agricultural chemical art, but which are novel and important becauseof the presence therein of the compounds of this invention. Somedescription of the formulation of the compositions will be given,however, to assure that agricultural chemists can readily prepare anydesired composition.

The dispersions in which the compounds are applied are most oftenaqueous suspensions or emulsions prepared from concentrated formulationsof the compounds. Such water-soluble, water-suspendable or emulsifiableformulations are either solids, usually known as wettable powders, orliquids usually known as emulsifiable concentrates or aqueoussuspensions. Wettable powders, which may be compacted to form waterdispersible granules, comprise an intimate mixture of the activecompound, an inert carrier, and surfactants. The concentration of theactive compound is usually from about 10% to about 90% by weight. Theinert carrier is usually chosen from among the attapulgite clays, themontmorillonite clays, the diatomaceous earths, or the purifiedsilicates. Effective surfactants, comprising from about 0.5% to about10% of the wettable powder, are found among the sulfonated lignins, thecondensed naphthalenesulfonates, the naphthalenesulfonates, thealkylbenzenesulfonates, the alkyl sulfates, and nonionic surfactantssuch as ethylene oxide adducts of alkyl phenols.

Emulsifiable concentrates of the compounds comprise a convenientconcentration of a compound, such as from about 50 to about 500 gramsper liter of liquid, equivalent to about 10% to about 50%, dissolved inan inert carrier which is either a water miscible solvent or a mixtureof water-immiscible organic solvent and emulsifiers. Useful organicsolvents include aromatics, especially the xylenes, and the petroleumfractions, especially the high-boiling naphthalenic and olefinicportions of petroleum such as heavy aromatic naphtha. Other organicsolvents may also be used, such as the terpenic solvents including rosinderivatives, aliphatic ketones such as cyclohexanone, and complexalcohols such as 2-ethoxyethanol. Suitable emulsifiers for emulsifiableconcentrates are chosen from conventional nonionic surfactants, such asthose discussed above.

Aqueous suspensions comprise suspensions of water-insoluble compounds ofthis invention, dispersed in an aqueous vehicle at a concentration inthe range from about 5% to about 50% by weight. Suspensions are preparedby finely grinding the compound, and vigorously mixing it into a vehiclecomprised of water and surfactants chosen from the same types discussedabove. Inert ingredients, such as inorganic salts and synthetic ornatural gums, may also be added, to increase the density and viscosityof the aqueous vehicle. It is often most effective to grind and mix thecompound at the same time by preparing the aqueous mixture, andhomogenizing it in an implement such as a sand mill, ball mill, orpiston-type homogenizer.

The compounds may also be applied as granular compositions, which areparticularly useful for applications to the soil. Granular compositionsusually contain from about 0.5% to about 10% by weight of the compound,dispersed in an inert carrier which consists entirely or in large partof clay or a similar inexpensive substance. Such compositions areusually prepared by dissolving the compound in a suitable solvent andapplying it to a granular carrier which has been pre-formed to theappropriate particle size, in the range of from about 0.5 to 3 mm. Suchcompositions may also be formulated by making a dough or paste of thecarrier and compound and crushing and drying to obtain the desiredgranular particle size.

Dusts containing the compounds are prepared simply by intimately mixingthe compound in powdered form with a suitable dusty agriculturalcarrier, such as kaolin clay, ground volcanic rock, and the like. Dustscan suitably contain from about 1% to about 10% of the compound.

It is equally practical, when desirable for any reason, to apply thecompound in the form of a solution in an appropriate organic solvent,usually a bland petroleum oil, such as the spray oils, which are widelyused in agricultural chemistry.

Insecticides and acaricides are generally applied in the form of adispersion of the active ingredient in a liquid carrier. It isconventional to refer to application rates in terms of the concentrationof active ingredient in the carrier. The most widely used carrier iswater.

The compounds of the invention can also be applied in the form of anaerosol composition. In such compositions the active compound isdissolved or dispersed in an inert carrier, which is apressure-generating propellant mixture. The aerosol composition ispackaged in a container from which the mixture is dispensed through anatomizing valve. Propellant mixtures comprise either low-boilinghalocarbons, which may be mixed with organic solvents, or aqueoussuspensions pressurized with inert gases or gaseous hydrocarbons.

The actual amount of compound to be applied to loci of insects, mites,and aphids is not critical and can readily be determined by thoseskilled in the art in view of the examples above. In general,concentrations of from 10 ppm to 5000 ppm by weight of compound areexpected to provide good control. With many of the compounds,concentrations of from 100 to 1500 ppm will suffice. For field crops,such as soybeans and cotton, a suitable application rate for thecompounds is about 0.5 to 1.5 lb/Acre, typically applied in 5-20 gal/Aof spray formulation containing 1200 to 3600 ppm of compound. For citruscrops, a suitable application rate is from about 100 to 1500 gal/A sprayformulation, which is a rate of 100 to 1000 ppm.

The locus to which a compound is applied can be any locus inhabited byan insect or arachnid, for example, vegetable crops, fruit and nuttrees, grapevines, and ornamental plants. Inasmuch as many mite speciesare specific to a particular host, the foregoing list of mite speciesprovides exemplification of the wide range of settings in which thepresent compounds can be used.

Because of the unique ability of mite eggs to resist toxicant action,repeated applications may be desirable to control newly emerged larvae,as is true of other known acaricides.

1. A compound of the formula (I)

wherein R¹ represents H, (C₁-C₆) alkyl, (C₁-C₆) haloalkyl, (C₂-C₆)alkenyl, (C₂-C₆) alkynyl, or (C₁-C₆) alkoxyalkyl; R³ represents H,halogen, (C₁-C₆) alkyl, (C₇-C₂₁) straight chain alkyl, hydroxy, (C₁-C₆)alkoxy, (C₁-C₆) haloalkyl, (C₁-C₆) haloalkoxy, (C₁-C₆) alkoxyalkyl,(C₁-C₆) alkoxyalkoxy, (C₂-C₆) alkenyl, (C₂-C₆) haloalkenyl, CN, NO₂,CO₂R⁶, CON(R⁶)₂, (C₃-C₆) cycloalkyl, S(O)_(m)R⁶, SCN, pyridyl,substituted pyridyl, isoxazolyl, substituted isoxazolyl, thienyl,substituted thienyl, thiazolyl, substituted thiazolyl, phenyl,substituted phenyl, —(CH₂)_(n)R⁶, —CH═CHR⁶, —C≡CR⁶, —CH₂OR⁶, —CH₂SR⁶,—CH₂NR⁶R⁶, —OCH₂R⁶, —SCH₂R⁶, —NR⁶CH₂R⁶,

R⁴ represents H, halogen, (C₁-C₆) alkyl, (C₁-C₆) alkoxy, (C₁-C₆)haloalkyl, (C₁-C₆) haloalkoxy, CN, CO₂R⁶, CON(R⁶)₂, (C₁-C₆) S(O)_(m)alkyl or (C₁-C₆) S(O)_(m) haloalkyl; R⁶ is H, (C₁-C₆) alkyl, (C₁-C₆)haloalkyl, (C₂-C₆) alkenyl, (C₂-C₆) alkynyl, phenyl, or substitutedphenyl; R⁷ and R⁸ are independently Cl or F; m is 0, 1, or 2; and n is 1or 2; or a phytologically-acceptable acid addition salt or N-oxidethereof or stereoisomers or mixtures thereof.
 2. A compound of claim 1in which R³ and each R⁴ independently represent H, halogen, (C₁-C₆)alkyl, (C₁-C₆) alkoxy, (C₁-C₆) haloalkyl or (C₁-C₆) haloalkoxy.
 3. Acompound of claim 1 in which R¹ represents H or methyl.
 4. A compound ofclaim 3 in which R¹ represents methyl and the compound consists ofindividual stereoisomers or mixtures thereof.
 5. A composition forcontrolling insects or mites which comprises a compound of claim 1 incombination with a phytologically-acceptable carrier.